Role of GAP-43 in mediating the responsiveness of cerebellar and precerebellar neurons to axotomy

To determine whether the competence for axonal sprouting and/or regeneratio n in the cerebellar system correlates with GAP-43 expression, we have studi ed GAP-43 mRNA and protein expression in the postlesioned cerebellum and in ferior olive. Purkinje cells transiently express GAP-43 during their develo pmental phase (from E15 to P5 in the rat) which consists of fast axonal gro wth and the formation of the corticonuclear projection. Adult Purkinje cell s, which in control adult rats do not express GAP-43, are extremely resista nt to the effects of axotomy but cannot regenerate axons. However, a late a nd protracted sprouting of axotomized Purkinje cells occurs spontaneously a nd correlates with a mild expression of GAP-43 mRNA. In contrast, inferior olivary neurons, despite their high constitutive expression of GAP-43, do n ot sprout but retract their axons and die after axotomy. Furthermore, matur e Purkinje cells in cerebellar explants of transgenic mice that overexpress GAP-43 do not regenerate after axotomy, even in the presence of a permissi ve substrate (cerebellar embryonic tissue) and, contrary to the case in wil d-type mice, they do not survive in the in vitro conditions and undergo mas sive cell death. These results show that the expression of GAP-43 is not on ly associated with axonal growth, but also with neuronal death.